New Data from ALXN1210 Dose-Escalation Study Presented at ASH Show Rapid and Sustained Reductions in LDH in
Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)
Recruitment Under Way in Multinational Phase 3 Trials of ALXN1210 Administered Every Eight Weeks in Patients
with PNH and Atypical Hemolytic Uremic Syndrome (aHUS)
Alexion Pharmaceuticals, Inc. (Nasdaq:ALXN) announced today that new data from an ongoing Phase 1/2 dose-escalation study of
ALXN1210 in patients with paroxysmal nocturnal hemoglobinuria (PNH) showed rapid and sustained reductions in lactate dehydrogenase
(LDH), a direct marker of hemolysis (the destruction of red blood cells), in patients treated with once-monthly dosing. In the
interim analysis of 13 patients, reductions in LDH were observed at the first evaluable time point (week 1) and were sustained over
the study analysis period of up to 24 weeks. Patients also had improvements in Functional Assessment of Chronic Illness Therapy
(FACIT)-Fatigue score from baseline, with patients in the higher-dose cohort achieving a two-fold greater improvement compared with
the lower-dose cohort.1 These findings were presented in a poster session at the 58th American Society of
Hematology (ASH) annual meeting in San Diego.
ALXN1210 is a highly innovative longer-acting anti-C5 antibody currently in Phase 3 trials in patients with PNH and atypical
hemolytic uremic syndrome (aHUS). PNH is a debilitating, ultra-rare blood disorder characterized by complement-mediated
hemolysis.2 In patients with PNH, the combination of LDH ≥1.5 times the upper limit of normal with any one of the
following clinical symptoms—abdominal pain, chest pain, dyspnea, hemoglobinuria, or fatigue—is associated with an increased risk of
thromboembolism, the leading cause of death in PNH.3 aHUS is a genetic, chronic, ultra-rare complement-mediated disease
associated with vital organ failure and premature death.4,5,6
“As the global leader in complement biology, Alexion is committed to achieving the highest levels of innovation to address the
needs of patients suffering from severe, ultra-rare complement-mediated disorders like PNH,” said Martin Mackay, Ph.D.,
Executive Vice President and Global Head of R&D at Alexion. “Results from the Phase 1/2 study of ALXN1210 presented at ASH
continue to support earlier findings that this highly innovative molecule has the potential to offer rapid, complete, and sustained
complement inhibition for patients suffering from the devastating effects of PNH. We are now focused on enrolling patients with PNH
and aHUS in our Phase 3 registration programs to evaluate ALXN1210 administered every eight weeks.”
Immediate, Complete, and Sustained Inhibition of C5 with ALXN1210 Reduces Complement-Mediated Hemolysis in Patients with
Paroxysmal Nocturnal Hemoglobinuria (PNH): Interim Analysis of a Dose-Escalation Study1
In a poster session, researchers presented interim results from the Phase 1/2, open-label, 24-week dose-escalating study of
ALXN1210 in patients with PNH. Initial findings from the study were previously reported at the 21st Congress of the
European Hematology Association (EHA) in June 2016, demonstrating that ALXN1210 achieved rapid and sustained LDH
reductions.7 The current analysis evaluated two cohorts of complement inhibitor-naïve patients with PNH (ages 18 and
older; n=13) who had mean LDH levels ≥3 times the upper limit of normal. Patients in Cohort 1 (n=6) received either 400 mg or 600
mg induction doses of ALXN1210, followed by a 900 mg maintenance dose once-monthly for a median of 5.6 months. Patients in Cohort 2
(n=7) received 600 mg and 900 mg induction doses of ALXN1210, followed by an 1800 mg maintenance dose once-monthly for a median of
4.6 months.
All patients showed rapid reductions in mean LDH levels at Week 1 (the first evaluable time point), which were sustained over
the study analysis period. As of the study analysis cutoff, treatment with ALXN1210 led to a mean reduction in LDH levels of 86
percent in Cohort 1 (baseline to Week 24) and 85 percent in Cohort 2 (baseline to Week 20). Four out of 6 patients in Cohort 1 (67
percent) and 4 out of 5 patients in Cohort 2 (80 percent) achieved LDH normalization, and 5 out of 6 patients in Cohort 1 (83
percent) and 5 out of 5 patients in Cohort 2 (100 percent) achieved mean LDH levels ≤1.5 times the upper limit of normal. Among
five patients with one or more transfusions in the year prior to the study, one patient in Cohort 1 required a transfusion, while
no patients in Cohort 2 required a transfusion with ALXN1210 treatment. In addition, mean levels of hemoglobin, another marker of
intravascular hemolysis, were improved or stable in both cohorts.
Researchers also presented patient-reported changes in fatigue, as measured by the FACIT-Fatigue Scale. From baseline to Week
24, mean FACIT-Fatigue score improved from 35.5 to 41.8 points (28.7 percent) for Cohort 1 and from 25.4 to 40.8 points (76.2
percent) for Cohort 2.
“In this interim analysis, ALXN1210 was associated with rapid and sustained reductions in LDH levels for up to six months in
patients with PNH. Notably, patients in the higher-dose cohort had a 2-fold greater improvement in FACIT-Fatigue score, as well as
no evidence of hemolysis or need for transfusion,” said lead author Jong-Wook Lee, M.D., Ph.D., Professor, Division of Hematology,
Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea. “These findings are consistent with a better hemolytic
response with the higher 1800 mg once-monthly dose and suggest that the 900 mg once-monthly dose may be inadequate in comparison
with 1800 mg for complete suppression of complement-mediated hemolysis.”
No serious adverse events or study withdrawals were observed in either patient cohort. The most common treatment-related adverse
event was headache, which occurred in four of 13 patients (30.8 percent) and resolved during ongoing treatment with ALXN1210.
About ALXN1210
ALXN1210 is a highly innovative, longer-acting anti-C5 antibody discovered and developed by Alexion that inhibits terminal
complement. In early studies, ALXN1210 demonstrated rapid, complete, and sustained reduction of free C5 levels.8 Alexion
has completed enrollment in two ongoing clinical studies of ALXN1210 in patients with PNH—a Phase 1/2 dose-escalating study and an
open-label, multi-dose Phase 2 study that is also evaluating longer dosing intervals beyond 8 weeks.
ALXN1210 is currently in Phase 3 trials in patients with PNH and aHUS. In addition, Alexion is conducting a Phase 1 study to
evaluate a new formulation of ALXN1210 administered subcutaneously in healthy volunteers.
In June 2016, the European Commission granted Orphan Drug Designation (ODD) to ALXN1210 for the treatment of patients with
PNH.
About Paroxysmal Nocturnal Hemoglobinuria (PNH)
PNH is an ultra-rare blood disorder in which chronic, uncontrolled activation of complement, a component of the normal immune
system, results in hemolysis (destruction of the patient's red blood cells). PNH strikes people of all ages, with an average age of
onset in the early 30s.2 Approximately 10 percent of all patients first develop symptoms at 21 years of age or
younger.9 PNH develops without warning and can occur in men and women of all races, backgrounds and ages. PNH often goes
unrecognized, with delays in diagnosis ranging from one to more than 10 years.10 In the period of time before treatment
was available, it had been estimated that approximately one-third of patients with PNH did not survive more than 5 years from the
time of diagnosis.11 PNH has been identified more commonly among patients with disorders of the bone marrow,
including aplastic anemia (AA) and myelodysplastic syndromes (MDS).12-14 In patients with thrombosis of unknown
origin, PNH may be an underlying cause.15
About Atypical Hemolytic Uremic Syndrome (aHUS)
aHUS is a chronic, ultra-rare, and life-threatening disease in which a life-long and permanent genetic deficiency in one or more
complement regulatory genes causes chronic uncontrolled complement activation, resulting in complement-mediated thrombotic
microangiopathy (TMA), the formation of blood clots in small blood vessels throughout the body.4,5 Permanent,
uncontrolled complement activation in aHUS causes a life-long risk for TMA, which leads to sudden, catastrophic, and
life-threatening damage to the kidney, brain, heart, and other vital organs, and premature death.4,6 Seventy-nine
percent of all patients with aHUS die, require kidney dialysis or have permanent kidney damage within three years after diagnosis
despite plasma exchange or plasma infusion (PE/PI).16 Moreover, 33-40 percent of patients die or progress to end-stage
renal disease with the first clinical manifestation of aHUS despite PE/PI.17,18 The majority of patients with aHUS who
receive a kidney transplant commonly experience subsequent systemic TMA, resulting in a 90 percent transplant failure rate in these
TMA patients.17
aHUS affects both children and adults. Complement-mediated TMA also causes reduction in platelet count (thrombocytopenia) and
red blood cell destruction (hemolysis). While mutations have been identified in at least ten different complement regulatory genes,
mutations are not identified in 40-50 percent of patients with a confirmed diagnosis of aHUS.16,17,19
About Alexion
Alexion is a global biopharmaceutical company focused on developing and delivering life-transforming therapies for patients with
devastating and rare disorders. Alexion is the global leader in complement inhibition and has developed and commercializes the
first and only approved complement inhibitor to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical
hemolytic uremic syndrome (aHUS), two life-threatening ultra-rare disorders. In addition, Alexion’s metabolic franchise includes
two highly innovative enzyme replacement therapies for patients with life-threatening and ultra-rare disorders, hypophosphatasia
(HPP) and lysosomal acid lipase deficiency (LAL-D). Alexion is advancing the most robust rare disease pipeline in the biotech
industry with highly innovative product candidates in multiple therapeutic areas. This press release and further information about
Alexion can be found at: www.alexion.com.
[ALXN-G]
Forward-Looking Statements
This press release contains forward-looking statements, including statements related to Alexion's development plans for
ALXN1210, the medical benefits of ALXN1210 for the treatment of PNH and aHUS, medical and commercial potential of ALXN1210, and
plans for regulatory filings for ALXN1210. Forward-looking statements are subject to factors that may cause Alexion's results and
plans to materially differ from those expected, including for example, decisions of regulatory authorities regarding marketing
approval or material limitations on the marketing of our products, delays, interruptions or failures in the manufacture and supply
of our products and our product candidates, progress in establishing and developing commercial infrastructure, failure to
satisfactorily address matters raised by the FDA and other regulatory agencies, the possibility that results of clinical trials are
not predictive of safety and efficacy results of our products in broader patient populations in the disease studied or other
diseases, the risk that strategic transactions will not result in short-term or long-term benefits, the possibility that current
results of commercialization are not predictive of future rates of adoption of Soliris in PNH, aHUS or other diseases, the
possibility that clinical trials of our product candidates could be delayed or that additional research and testing is required by
regulatory agencies, including for ALXN1210, the adequacy of our pharmacovigilance and drug safety reporting processes, the risk
that third party payors (including governmental agencies) will not reimburse or continue to reimburse for the use of our products
at acceptable rates or at all, risks regarding government investigations, including investigations of Alexion by the SEC and DOJ,
risks relating to the internal investigation being conducted by the Audit and Finance Committee, the risk that anticipated
regulatory filings are delayed, including for ALXN1210, the risk that estimates regarding the number of patients with PNH, aHUS,
HPP and LAL-D are inaccurate, the risks of shifting foreign exchange rates, and a variety of other risks set forth from time to
time in Alexion's filings with the U.S. Securities and Exchange Commission, including but not limited to the risks discussed in
Alexion's Quarterly Report on Form 10-Q for the period ended June 30, 2016 and in our other filings with the U.S. Securities and
Exchange Commission. Alexion does not intend to update any of these forward-looking statements to reflect events or circumstances
after the date hereof, except when a duty arises under law.
|
|
References
|
|
|
|
|
|
|
|
|
|
1. |
|
Lee JW, Bachman ES, Aguzzi R, et al. Immediate, complete, and sustained inhibition of
C5 with ALXN1210 reduces complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH): interim
analysis of a dose-escalation study (Abstract 2428). Poster presented at the 58th annual meeting of the American
Society of Hematology (ASH), San Diego, California, December 3-6, 2016. |
|
|
|
2. |
|
Socié G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria:
long-term follow-up and prognostic factors. Lancet. 1996: 348:573-577. |
|
|
|
3. |
|
Lee JW, Jang JH, Kim JS, et al. Clinical signs and symptoms associated with increased risk
for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry. Int J Hematol. 2013
Jun;97(6):749-57.
|
|
|
|
4. |
|
Benz K, Amann K. Thrombotic microangiopathy: new insights. Curr Opin Nephrol
Hypertens. 2010;19(3):242-247. |
|
|
|
5. |
|
Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial
therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24:687-696. |
|
|
|
6. |
|
Tsai HM. The molecular biology of thrombotic microangiopathy. Kidney Int.
2006;70(1):16-23. |
|
|
|
7. |
|
Lee JW, Bachman E, Aguzzi R, et al. ALXN1210, a long-acting C5 inhibitor, results in
rapid and sustained reduction of LDH with a monthly dosing interval in patients with PNH: preliminary data from a
dose-escalation study (Abstract 4126). Poster presented at 21st Congress of the European Hematology Association (EHA),
Copenhagen, Denmark, June 9-12, 2016. Abstract 4126. |
|
|
|
8. |
|
Sahelijo L, Mujeebuddin A, Mitchell D, et al. First in human single-ascending dose
study: safety, biomarker, pharmacokinetics and exposure-response relationships of ALXN1210, a humanized monoclonal antibody to
C5, with marked half-life extension and potential for significantly longer dosing intervals. Blood. 2015;126 (23):4777. |
|
|
|
9. |
|
Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal
nocturnal hemoglobinuria. Blood. 2005;106(12):3699-3709. |
|
|
|
10. |
|
Dacie JV, Lewis SM. Paroxysmal nocturnal haemoglobinuria: clinical manifestations,
haematology, and nature of the disease. Ser Haemat. 1972;5:3-23. |
|
|
|
11. |
|
Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal
nocturnal hemoglobinuria. N Engl J Med. 1995;333(19):1253-1258. |
|
|
|
12. |
|
Wang H, Chuhjo T, Yasue S, Omine M, Naka S. Clinical Significance of a minor
population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome. Blood.
2002;100(12):3897-3902. |
|
|
|
13. |
|
Iwanga M, Furukawa K, Amenomori T, et al. Paroxysmal nocturnal hemoglobinuria clones
in patients with myelodysplastic syndromes. Br J Haematol. 1998;102(2):465-474. |
|
|
|
14. |
|
Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS. Relationship between bone marrow
failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones. Br J Haematol.
2001;115:1015-1022. |
|
|
|
15. |
|
Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria.
Blood. 2013;121:4985-4996. |
|
|
|
16. |
|
Fremeaux-Bacchi, et al. Genetics and Outcome of Atypical Hemolytic Uremic Syndrome: A
Nationwide French Series Comparing Children and Adults. Clin J Am Soc Nephrol. 2013 Apr 5; 8(4): 554–562. |
|
|
|
17. |
|
Noris M, Caprioli J, Bresin E, et al. Relative Role of genetic complement
abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5:1844-59. |
|
|
|
18. |
|
Caprioli J, Noris M, Brioschi S, et al; for the International Registry of Recurrent
and Familial HUS/TTP. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to
treatment, and outcome. Blood. 2006;108:1267-1279. |
|
|
|
19. |
|
Bresin E, et al. Combined Complement Gene Mutations in Atypical Hemolytic Uremic
Syndrome Influence Clinical Phenotype. J Am Soc Nephrol. 2013;24: 475-486. |
|
|
|
|
|
|
|
Alexion Pharmaceuticals, Inc.
Media
Stephanie Fagan, 475-230-3777
Senior Vice President, Corporate Communications
or
Kim Diamond, 475-230-3775
Executive Director, Corporate Communications
OR
Investors
Elena Ridloff, CFA, 475-230-3601
Vice President, Investor Relations
View source version on businesswire.com: http://www.businesswire.com/news/home/20161204005031/en/